Expansion of CAG/CTG repeats in DNA is the underlying cause of >14 genetic disorders, including Huntington disease (HD) and myotonic dystrophy. The mutational process is ongoing, with increases in repeat size enhancing the toxicity of the expansion in specific tissues. In many repeat diseases, the repeats exhibit high instability in the striatum, whereas instability is minimal in the cerebellum. In recent work, we have provided molecular insights into how BER protein stoichiometry may contribute to the tissue-selective instability of CAG/CTG repeats by using specific repair assays. In particular, repair efficiency at CAG/CTG repeats and at control DNA sequences was markedly reduced under conditions that mimic the striatal situation, likely because of lower levels of the proteins APE1, FEN1, and LIG1. Moreover, damage located toward the 5' end of the repeat tract was poorly repaired, with the accumulation of incompletely processed intermediates as compared to an abasic lesion in the center or at the 3' end of the repeats or within control sequences. In addition, repair of lesions at the 5' end of CAG or CTG repeats involved multinucleotide synthesis, particularly at the cerebellar stoichiometry, suggesting that long-patch BER processes lesions at sequences susceptible to hairpin formation. Our results show that the BER stoichiometry, nucleotide sequence, and DNA damage position modulate repair outcome and suggest that a suboptimal long-patch BER activity promotes CAG/CTG repeat instability. More recently, we have found that the BER DNA glycosylase NEIL1 contributes to germline and somatic CAG repeat expansion in HD. Single-strand break repair (SSBR) is an important subpathway of BER. Recent data has found a genetic linkage between proteins of SSBR aprataxin, tyrosyl-DNA phosphodiesterase 1 and DNA polynucleotide kinase phosphatase and human neurological disorders, implicating this process in protection against neuronal cell loss and brain function. Ataxia with oculomotor apraxia 1 (AOA1) is caused by mutation in the APTX gene, which encodes the stand break repair protein aprataxin. Aprataxin removes 5-adenylate groups in DNA that arise from aborted ligation reactions. AOA1 is characterized by global cerebellar atrophy, highlighted by loss of Purkinje cells, ocular motor apraxia, and motor and sensory neuropathy. Strikingly, AOA1 patients lack the cancer susceptibility and other peripheral symptoms (e.g., immunological deficiencies) commonly associated with other inherited disorders stemming from a DNA repair defect. We have reported that aprataxin activity is indispensable for maintaining mitochondrial function, indicating that there is likely a mitochondrial component to the disease phenotype of AOA1. Moreover, our data indicate that because of their higher BER capacity, proliferative neural progenitor cells are more efficient at repairing DNA damage compared with their neuronally differentiated progeny. Future studies are aimed at determining the reason behind the tissue selectivity of AOA1, with an eye towards differential repair capacity as a key factor. Cockayne Syndrome (CS) is an autosomal recessive disorder, characterized by growth failure, neurological abnormalities, premature aging symptoms, and cutaneous photosensitivity, but no increased cancer incidence. CS is divided into two strict complementation groups: CSA (mutation in CKN1) and CSB (mutation in ERCC6). Of the patients suffering from CS, 80% have mutations in the CSB gene. We are pursuing the hypothesis that the primary role of CS proteins is to facilitate the repair of endogenous DNA damage, and we have evidence for a direct role of CSB in regulating BER efficiency. Our in vitro work has also helped define the biochemical properties of CSB, revealing that the protein interacts with a diverse range of nucleic acid substrates and likely has important ATP-dependent and ATP-independent functions. More recent results, obtained in collaboration with Dr. Vilhelm Bohr, suggest that CSB plays a direct role in not only nuclear BER, but in mitochondrial BER, likely by helping recruit, stabilize, and/or retain BER proteins in repair complexes associated with the inner mitochondrial membrane. Moreover, CSB appears to act as a mitochondrial DNA damage sensor, inducing mitochondrial autophagy in response to stress, and thus, pharmacological modulators of autophagy are potential treatment options for this accelerated aging phenotype. CSB-deficient cells also exhibit a defect in efficient mitochondrial transcript production and the CSB protein specifically promotes elongation by the mitochondrial RNA polymerase suggesting that the pathologies associated with CS are in part, a direct result of the roles that CSB plays in mitochondria. Future work will aim to determine the biological substrates and molecular role(s) of the CS proteins in endogenous DNA damage repair.